p73α Regulation by Chk1 in Response to DNA Damage

Abstract

The checkpoint kinase 1 (Chk1) is an essential component of the DNA damage checkpoint. Previous studies have demonstrated an indispensable role for the p53-related transcription factor p73α in DNA damage-induced apoptosis. Here, we provide evidence that p73α is a target of Chk1. We found that endogenous p73α is serine phosphorylated by endogenous Chk1 upon DNA damage, which is a mechanism required for the apoptotic-inducing function of p73α. Consistent with this, we discovered that endogenous p73α interacts with Chk1 and is phosphorylated by Chk1 at serine 47 in vitro and in vivo. In contrast, Chk2 does not phosphorylate p73α in vitro. Moreover, mutation of serine 47 abolishes both Chk1-dependent phosphorylation of p73α upon DNA damage in vivo and the ability of Chk1 to upregulate the transactivation capacity of p73α. Our data indicate a novel biochemical pathway through which the p73α proapoptotic function requires DNA damage-triggered p73α phosphorylation by Chk1.